Multifunctional Hyaluronic Acid-Modified Pterostilbene Nanoliposomes for Enhanced Dermal Delivery and Extracellular Matrix Protection

Background: Skin aging involves extracellular matrix (ECM) deterioration, including collagen loss and disrupted glycosaminoglycan and proteoglycan homeostasis. Pterostilbene (PTE) has antioxidant and anti-inflammatory activity, but its topical use is limited by poor aqueous solubility and limited skin delivery. We developed hyaluronic acid (HA)-modified, PTE-loaded nanoliposomes (HA-LP-PTE) and evaluated their association with dermal fibroblasts, retention in skin, and effects on ECM-related responses. Methods: HA-LP-PTE was prepared by high-pressure microfluidization and assessed for size, morphology, zeta potential, and encapsulation efficiency. Fluorescence microscopy was used to examine fibroblast-associated fluorescence of FITC-labeled HA-LP-PTE and non-HA-modified PTE-loaded liposomes (LP-PTE). Skin retention was assessed using Franz diffusion cells. ECM-related changes were analyzed in UV-irradiated ex vivo skin and fibroblasts using staining techniques and RT-qPCR. Results: HA-LP-PTE had a mean diameter of 55.44 ± 0.81 nm, a polydispersity index of 0.120 ± 0.009, and an encapsulation efficiency of 99.34 ± 0.51%. At 4 h, fibroblast-associated fluorescence was higher than with LP-PTE (p = 0.040) and was reduced by free HA or incubation at 4 °C. After 12 h, dermal PTE retention was 4.08-fold higher than free PTE and 1.74-fold higher than LP-PTE. HA-LP-PTE increased all six ECM components examined. Chondroitin sulfate and perlecan met the Q criterion for synergy, and several ECM synthesis-related genes were upregulated. Conclusions: HA modification improved PTE delivery beyond liposomal encapsulation alone, with greater fibroblast-associated fluorescence and higher PTE retention in viable skin than LP-PTE. ECM and gene-expression findings also indicated matrix-related activity. HA-LP-PTE may enhance topical PTE delivery and attenuate UV-induced ECM loss.